Three distinct glucose transporter isoforms have been detected in mammalian brain. A 55kDa GLUT1 isoform is the primary transporter in the blood-brain barrier. A lower molecular weight GLUT1 (45kDa) has been observed in vessel-free cortex and is presumably of neuronal and or glial origin. We have previously shown that GLUT3 is present in primary neuronal cultures and more recently in situ hybridization studies have confirmed its presence in neurons in intact tissue. Most recently, we, in collaboration with Dr. Peter Davies, have detected GLUT5 immunohistochemically in human microglia and also in human monocytes following their differentiation into tissue macrophages. One of the major objectives of our studies has been to investigate what effects diabetes has on the region-specific expression of these glucose transporters in brain. We have employed two animal models of diabetes: l) the streptozotocin-treated rat and, 2) in conjunction with Dr. Robert Sherwin at Yale University, the BB-Wistar rat. In the first model we found a diabetes-induced increase (20%) in the level of GLUT3 protein in the neurohypophysis which was detected by day 3 following administration of streptozotocin and persisted through four weeks. Conversely,GLUT1 was decreased by 20% by day 3 and was 53% of the control level at 4 weeks.This represents the first demonstration of stress-related regulation of GLUT3 expression. In the BB-Wistar rats we studied the effects of diabetes and episodic hypoglycemia on region-specific glucose transporter expression. In the diabetic animals the levels of GLUT1 were increased 18-63% in temporal cortex, frontal cortex, hippocampus and brain stem and decreased in cerebellum (10%) and pineal (40%). GLUT3 was found to be increased (18- 38%) in hippocampus, brain stem and neurohypophysis. However, recurrent hypoglycemia had no effect on the expression of either GLUT1 of GLUT3 in either control or diabetic animals. Thus, in contrast to peripheral tissues where there is a down-regulation of transporters associated with diabetes, in brain an up-regulation is observed.